Alfred G. Knudson Jr, MD, Phd: in Memoriam (1922–2016) Jonathan Chernoff

Cancer Obituary Research

Alfred G. Knudson Jr, MD, PhD: In Memoriam (1922–2016) Jonathan Chernoff

One can hardly open an issue of Cancer Research without He continued his clinical work in pediatrics at an Army Base finding a half-dozen or more articles that address the role of during the Korean War, returning to the California Institute of various tumor suppressor genes in cancer. We now take it for Technology for his PhD. granted that cancer is, at its core, a genetic disease and that one of After an initial faculty appointment at the City of Hope Medical the most important ways that mutations in DNA induce malig- Center in California, Knudson became the Associate Dean for nant transformation is through damage to both alleles of tumor Basic Sciences at the State University of New York at Stony Brook suppressor genes. Although many scientists over many decades Health Sciences Center (Stony Brook, NY). In 1969, he moved to contributed to building this model, its chief architect was Alfred M.D. Anderson Cancer Center (Houston, TX), and it was there, G. Knudson, Jr, MD, PhD. while serving as Dean of the Graduate School of Biomedical When Knudson died at 94 on July 10, 2016, the field of cancer Sciences, that he developed his revolutionary ideas about herita- genetics lost one of its true giants. With tools no more sophisti- ble cancers. In 1976, he joined Fox Chase Cancer Center in cated than pencil and paper, he proposed a quantitative mech- Philadelphia, PA, where he held the positions of Director of the anism to explain how inherited damage to genes could lead to Institute for Cancer Research and Center President. cancer. First formalized as the "two-hit" theory in 1971, this idea Knudson would have thrived in any academic environment, remains perhaps the single most influential paradigm in all of but he made an inspired choice by coming to Fox Chase, where cancer genetics, essential for understanding the origins of hered- he had daily contact with an extremely talented group of collea- itary and sporadic malignancies. In terms of its simplicity, power, gues that included, among others, Barry Blumberg, Jenny Glusker, and influence, his work can justly be compared with that of the Bea Mintz, Bob Perry, Ernie Rose, and Anne Skalka. Even among 19th century geneticist Gregor Mendel, whose famous pea garden that rarefied group, many considered Knudson primus inter pares. in Brno was a must-see pilgrimage site when Knudson visited Presenting a seminar to an audience that included such esteemed Czechoslovakia in the 1970s. scientists could be a formidable challenge, but his gentle nature During his youth, Knudson had a strong interest in and knowl- ensured that even the greenest investigator was treated as a edge of mathematics and physics, and these interests served him scientific equal. The nature of his enquiry was deep and the well when he later turned to genetics. His college years at the questions he posed required careful thought, often prompting California Institute of Technology (Pasadena, CA) no doubt new lines of research. spurred his interest in this area, as he encountered professors Regarding his scientific legacy, Knudson was first and foremost such as Thomas Hunt Morgan, Alfred Sturtevant, and Linus a pediatrician, and he viewed the cancer genetics problem though Pauling and began a lifelong friendship with Ed Lewis, who was the lens of pediatric cancers, in particular, the hereditary cancer a graduate student at that time. He then received his MD from syndromes. His insights that led to the two-hit theory did not Columbia University (New York, NY) and, key to all that fol- require a single laboratory-based experiment, but were instead lowed, subsequently did a residency in pediatrics at New York derived from an analysis of patient records, the age of onset of Hospital (New York, NY) that included a stint at the pediatric unit retinoblastoma, and the extent of disease in hereditary versus of the Memorial Sloan Kettering Cancer Center (New York, NY). sporadic cases. From these clinical records, he deduced that children with heritable cases of retinoblastoma must have been born with a mutation in one allele of a gene that normally restrains cell growth and/or survival, and that, in such children, Fox Chase Cancer Center, Philadelphia, Pennsylvania. only one additional "hit" to the remaining allele would be Corresponding Author: Jonathan Chernoff, Fox Chase Cancer Center, 333 required to initiate tumor formation. Sporadic cases were not Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-5319; Fax: 215-728- hereditary because two mutations in such growth-restraining 3616; E-mail: [email protected] genes were required in a somatic cell. Others had previously doi: 10.1158/0008-5472.CAN-16-3547 proposed various models to explain multistage mechanisms for Ó2017 American Association for Cancer Research. carcinogenesis, but Knudson's two-hit theory differed in that it

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provided a quantitative method by which one could infer under- Although best known for his work on cancer genetic theory, lying processes of tumor incidence and progression and that, at now enshrined in standard textbooks on the topic, Knudson also least in retinoblastoma, only two mutations were required to had success in the experimental realm. For example, with his breach the barriers for tumorigenesis. colleagues Ray Yeung and Joe Testa at Fox Chase, he was able to The theory proved such a success that it is today nearly impos- identity a germline loss-of-function mutation in the Tsc2 gene sible to discuss cancer in the absence of the framework provided as the cause of hereditary renal cell carcinoma in the Eker rat by the now-famous Knudson two-hit hypothesis. However, what model. Also, toward the end of his career, he assembled a team to seems obvious and intuitive now was hardly the case in the late examine how gene expression changes in cells from at-risk family 1960s and early 1970s, when various inherited cancer syndromes members who had inherited one-hit damage to the VHL or TSC were recognized but their genetic mechanisms not understood. It tumor suppressor genes. This work resulted in his final publica- took several of Knudson's special gifts—a talent and interest in tion, published in Oncotarget just months before his death, with mathematics, an intense interest in pediatric cancers (in which he Knudson as the senior author. correctly assumed the mutational load would be lower than in Knudson's influence extended beyond his direct contribu- adult cancers), and a deep understanding of genetics—to formu- tions to science. He held high-level administrative positions for late the two-hit hypothesis, as well as the patience to wait the most of his career and was perforce no stranger to the hurly- nearly 15 years it would take for cloning techniques to evolve burly of academic politics, but he was a most unusual bureau- to the point that it became possible to isolate actual tumor crat. His oft-stated motto was that he cared far more about suppressor genes, or "anti-oncogenes," as he initially called them. "ideas per square foot" than "dollars per square foot," and he Fittingly, the first of these to be mapped and cloned was the Rb meant what he said. If one had a sufficient quantity of the gene, whose existence and behavior he had postulated in 1971. It former, the latter was deemed relatively unimportant and he and the dozens of tumor suppressor genes that were cloned soon would find a way to assist in funding. Indeed, in one well- thereafter, for the most part, behaved just as he had predicted they known incident, recounted in his obituary in the NY Times on would. Damage to both alleles was required to fully disable the July 14, 2016, Knudson's prescient support was critical in brakes on cancer cell growth. assembling the 3-man team that discovered the ubiquitin For these achievements, Knudson received many of the most pathway for protein destruction. In this case, he asked the Fox prestigious awards in Biology, including, among many others, the Chase financial director for the princely sum of $50,000 to be Lasker Prize, the Kyoto Prize, and the General Motors Prize. Had a set aside to support the salaries of Hershko and Ciechanover Nobel Prize in Medicine been awarded for the discovery of tumor during their sabbatical in Rose's laboratory in 1979, because suppressor genes, as it someday surely will be, there is little doubt their work "will surely have great implications for develop- that he would have won that too. mental process, for normal physiology, and for cell death and Knudson was the quintessential "big picture" scientist, with a cancer. The implications are enormous ..."Asinmanyother rare talent for distilling scientific problems to their essence. For areas, his instincts in this case were correct, and this team went example, he had a lifelong interest in the phakomatosis syn- on to win the Nobel Prize in 2004. dromes and was convinced that these were fundamentally linked No tribute to Knudson would be complete without the at the molecular level and that, eventually, we would be able to mention of a loving partner in his work, his wife Dr. Anna place all the proteins encoded by these genes into a single, Meadows. Renowned in her own right for her contributions to comprehensive wiring diagram that explained the pathophysiol- pediatric cancer survivorship, Meadows was an intellectual foil ogy of these syndromes. Thus, it was with great pleasure that he against whom Knudson could test his ideas, and she was not lived to see the cloning of the tumor suppressor genes that are lost afraid to challenge them. She remained a constant source of in von Hippel–Lindau (VHL), tuberous sclerosis (TSC), Cowden support through the many years of their marriage, and she disease, neurofibromatosis I, and Peutz–Jeghers syndrome, and joined him in his extra-scientific cultural interests of art, music, how their gene products interact with one another in cells. The and travel. construction of a "grand unification theory" for the tumor sup- Al will be sorely missed by his colleagues at Fox Chase, his pressor genes so engrossed him that it was the rare conversation friends and family, and by the scientific community at large. about science that did not eventually turn to this weighty subject. The many scientists and physicians whose lives he influenced And, drum roll please, his intuition was again correct: Many of the will continue to carry out his legacy for many years to come. tumor suppressor gene-encoded proteins involved in the phakomatosis syndromes are indeed linked in a signaling pathway that Received December 27, 2016; accepted December 27, 2016; published online explains certain common features of these disorders. February 15, 2017.

816 Cancer Res; 77(4) February 15, 2017 Cancer Research

Jonathan Chernoff

Cancer Res 2017;77:815-816.

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